Recently, MDMA (3,4-methylenedioxymethamphetamine; 'Ecstasy') has become a much studied designer drug because of its unique pharmacological/behavioral profiles, abuse potential and neurotoxicity. It is a ring-substituted phenylisopropylamine which is chemically related to amphetamine, a central stimulant, and mescaline, a hallucinogen. However, MDMA's pharmacological and behavioral profiles do not completely mimic those produced by these compounds. Data from human subjects indicate that MDMA appears to enhance emotion and cognition but is nonhallucinogenic. It is now known that MDMA releases and blocks the uptake of serotonin (5-hydroxytryptamine, 5-HT) and perhaps, to a much lesser extent, dopamine (DA) in the brain. This drug also inhibits the activity of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of 5HT. In addition, MDMA binds 5-HT(1) and 5-HT(2) receptors with low micromolar affinity and DA receptors with even lower affinity. Presumably the released neurotransmitters interact with receptors localized on neurons innervated by the 5-HT and perhaps DA fibers to elicit the behavioral effects of MDMA. However, the precise location and action of MDMA is not yet known. The specific aim of this proposal is to investigate the mode of action of MDMA on neurons in the medial prefrontal cortex and the nucleus accumbens of chloral hydrate anesthetized rats using the techniques of extracellular single unit recording and microiontophoresis. These brain areas have dense 5-HT and DA innervation and play a significant role in emotion and cognition. We will determine the relative contribution of the 5-HT and DA-releasing properties of MDMA in mediating its effect in these brain regions by studying the effect of depleting and replenishing the content of 5-HT and DA in the brain on MDMA's action. Then we will assess the relative importance of activating the specific subtypes of 5-HT and DA receptors in achieving MDMA's unique psychopharmacological profile. This will be accomplished by the systematic examination of the ability of various specific 5-HT and DA receptor antagonists in blocking or reversing the MDMA-induced effects. Furthermore, structure-activity relationship of the phenylisopropylamines will be explored by comparing the effects of closely related analogues. Information from this study will improve our understanding of the mode of action of MDMA and other phenylisopropylamines.